N6-methyladenosine (m6A) methyltransferase METTL3 regulates sepsis-induced myocardial injury through IGF2BP1/HDAC4 dependent manner
Hao Shen, Keliang Xie, Miaomiao Li, Qianyu Yang, Xiaoye Wang
Abstract
Abstract Recent studies have identified that N 6 -methyladenosine (m 6 A) extensively participates in the myocardial injury pathophysiological process. However, the role of m 6 A on sepsis-induced myocardial injury is still unclear. Here, we investigated the functions and mechanism of m 6 A methyltransferase METTL3 for septic myocardial injury. Results illustrated that the m 6 A modification level and METTL3 up-regulated in the lipopolysaccharide (LPS)-induced cardiomyocytes (H9C2 cells). Methylated RNA immunoprecipitation sequencing (MeRIP-Seq) revealed the m 6 A profile of the septic myocardial injury cellular model. Functionally, METTL3 knockdown repressed the inflammatory damage of cardiomyocytes induced by LPS. Mechanistically, we found that HDAC4 had remarkable m 6 A modification sites on its 3’-UTR genome, acting as the downstream target of METTL3. Besides, m 6 A reader IGF2BP1 recognized the m 6 A modification sites on HDAC4 mRNA and enhanced its RNA stability. In conclusion, the findings illustrated a role of METTL3/IGF2BP1/m 6 A/HDAC4 axis on sepsis-induced myocardial injury, which might provide novel therapeutic strategy for septic myocardial injury.